The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes

Robert Huether, Li Dong, Xiang Chen, Gang Wu, Matthew Parker, Lei Wei, Jing Ma, Michael N. Edmonson, Erin K. Hedlund, Michael C. Rusch, Sheila A. Shurtleff, Heather L. Mulder, Kristy Boggs, Bhavin Vadordaria, Jinjun Cheng, Donald Yergeau, Guangchun Song, Jared Becksfort, Gordon Lemmon, Catherine WeberZhongling Cai, Jinjun Dang, Michael Walsh, Amanda L. Gedman, Zachary Faber, John Easton, Tanja Gruber, Richard W. Kriwacki, Janet F. Partridge, Li Ding, Richard K. Wilson, Elaine R. Mardis, Charles G. Mullighan, Richard J. Gilbertson, Suzanne J. Baker, Gerard Zambetti, David W. Ellison, Jinghui Zhang, James R. Downing

Research output: Contribution to journalArticlepeer-review

301 Scopus citations


Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.

Original languageEnglish
Article number3630
JournalNature communications
StatePublished - Apr 8 2014


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